DESCRIPTION (taken from the application) Both insulin resistance and insulin deficiency have been implicated in the pathogenesis of type 2 diabetes, although the relative contribution of each process remains in dispute. In an attempt to define the evolution of pre-Type 2 diabetes, two study cohorts were identified between 1963-1983, one composed of offspring of two type 2 diabetic parents (FH+) with a high genetic risk of diabetes, the second of individuals with no family history of diabetes (FH-). All subjects had normal oral glucose tolerance at study entry and underwent intravenous glucose tolerance testing analyzed using the Bergman Minimal Model. Low insulin sensitivity (SI) and low glucose effectiveness (SG) were demonstrated to precede and predict the development of type 2 diabetes in FH+ subjects. Preliminary work revealed that when matched for severity of insulin resistance at study entry, low SI and low SG did not precede or predict diabetes in age matched FH- adults. During 25 + 6 yrs. follow-up, comprising 2,758 person-years, the FH- controls had an overall, age-adjusted incidence rate of type 2 diabetes of 1.8 per 1000 person years, about one tenth that for FH+ (16.7 per 1000 person years). When the two study populations were subdivided by SI and SG, there was a 5-10 fold greater age adjusted difference in incidence rate for the development of disease for FH+ individuals with low SI (i.e. insulin resistant) than for FH- subjects with similar S, Insulin secretory capacity, assessed by Phi-1 and Phi-2 at a time when all individuals were normoglycemic, was not predictive for development of diabetes in either group. The hypothesis is that a genetic factor other than those assessed by the minimal model accounts for the striking difference in risk of type 2 diabetes in subjects who are FH+ as compared to FH-. The goal is to identify changes in glucose metabolism specifically related to the pre-diabetic condition in FH+ matched by low SI and low SG to FH-. Also, insulin sensitive FH+ and FH- will be studied to evaluate the independent impact of insulin resistance on glucose metabolism. Specifically, we will evaluate 1) differences in the hyperbolic relationship of insulin secretion and insulin resistance between the cohorts; 2) beta cell function with measurements of pulsatile insulin secretion; 3) mechanisms of insulin resistance during two step euglycemic-hyperinsulinemic clamp studies including differences in splanchnic vs. peripheral resistance; kinetics of insulin suppression of FFA and FFA turnover with 13C-palmitate; and compare oxidative and non-oxidative glucose and fatty acid metabolism with indirect calorimetry; 4) quantitative and functional differences in insulin signaling proteins including the insulin receptor, the IRS protein family, PI-3-kinase, and phosphoprotein phosphatases in adipose and muscle tissue samples 5) using gene chip technology search for factors responsible for insulin resistance and for genetic susceptibility to type 2 diabetes. The physiologic changes will be related to functional changes in proteins involved in signal transduction and to genomic mutations specific to the disease. Rigorous clinical characterization of pre-diabetic compared to non-prediabetic insulin resistant populations will determine the earliest pathophysiology of this disorder and may lead to new treatments in the prevention of this common disease.